A Modular DNA Hydrogel Vaccine with Optimized Nanoadjuvants and Tumor Targeting Capacity

ABSTRACT DNA hydrogels have garnered attention as smart nanomaterials due to their exceptional editability, inherent biodegradability, and tunable multifunctionality, enabling structural responses to diverse stimuli. This study developed a DNA‐polyacrylamide nanogel cancer vaccine (designated DPCV). Upon reaching the acidic tumor microenvironment (TME) and endosomes, i‐motif formation triggers gradual dissociation of DPCV, releasing adjuvants, aptamers, and chemotherapeutic drugs. While ablating the tumor, DPCV inducing robust immunogenic cell death (ICD), releasing tumor antigens that ultimately activate antigen presentation and antitumor‐specific immune responses. In coculture systems, DPCV promoted DC maturation and associated cytokines IL‐6 and IL‐12 secretion in the supernatant, and enhanced T cell activation, elevating IL‐2 secretion. In orthotopic breast and pancreatic tumor mouse models, DPCV markedly suppressed tumor growth, reduced metastasis, and increased intratumoral CD8 + T cell infiltration. In postoperative tumor‐resection models, DPCV reduced tumor recurrence, while generating durable immune memory characterized by increased central memory T cells and effector memory T cells in both tumors and spleens. DPCV combined precise delivery, controlled release, potent immunostimulatory activity, and significant synergistic therapeutic benefits, while minimizing treatment‐associated side effects. It holds promising potential for clinical translation.